7]. Bioabsorbable drug-­eluting stents have the potential advantage of reducing the risk of stentrelated complications, but they have only been studied in animal models of benign tracheal stenosis [1]. In animal models, novel bioabsorbable stents (made of polycaprolactone) with cisplatin elution have been developed to overcome some of the problems associated with chronic indwelling stents (tumor ingrowth, fracture, migration) [8]. The mechanical strength of these stents was shown to be comparable to the strength of Ultrafex self-expandable metallic stents (SEMS) and provided a steady release of cisplatin for >4 weeks in vitro. The in vivo study showed sustained cisplatin levels in rabbit trachea for >5 weeks with a minimum drug level in blood. Histologic examination showed an intact ciliated epithelium and marked leukocyte in ltration in the submucosa of the stented area, ndings suggesting potential use in malignant CAO. In a human study, six biodegradable polydioxanone tracheal stents were safely implanted in four patients with benign inoperable tracheal stenosis. The authors report that all patients had “some” bene t from treatment and suggested that further research is needed to fully assess the outcomes of this therapy [9]. Biodegradable stents have been used in airway compression caused by vascular compression in pediatric population [10]. However, their safety remains of concern since degradation fragments can lead to airway obstruction [11]. Despite the limited clinical experience, 3D printed stents can represent a more patient-focused alternative to manage CAO. These stents consist in patient-­speci c silicone airway stents generated using computed tomography (CT) imaging and 3D printing technology. Gildea et al. reported improved durability, improvement in patient-­reported symptoms leading to a reduced need for stent changes, and modi cations in two patients with granulomatosis with polyangiitis (GPA) at 1 year follow-up [12]. Whether these stents will be incorporated into clinical practice remains to be determined. One concern is the lack of their availability at the time of the procedure. This makes them impractical as additional procedures are necessary since the CT scanning is performed post-debulking/dilation.

Airway bioengineering using stented aortic matrices implantation is a novel concept and was

shown to be clinically feasible. In a study of 13 patients, 8 had normal breathing through newly formed airways after stent removal at 3-year fol- low-­up. More studies are needed to assess the ef cacy and safety of this technique [13].

As of this writing, the original described problems of migration, granulation, mucus plugging, infection, and even airway perforation and fatal hemoptysis are still present after stent insertion [14]. Therefore, operators have to carefully review the indications and expected results before inserting airway stents.

Indications

Airway stents are most commonly used for symptomatic extrinsic airway compression with or without associated airway mucosal in ltration. Stents can also be used if there is still signi cant (generally considered more than 50%) narrowing after the endoluminal component of a purely exophytic or mixed type of obstruction has been treated using one or more bronchoscopic techniques2 [15]. Various stents have been used as well for sealing malignant, inoperable benign esophagorespiratory, and bronchial stump stulas. Stents are occasionally used to improve symptoms of severe crescent type tracheobronchomalacia and excessive dynamic airway collapse, in patients who are refractory to more conservative measures (i.e., continuous positive airway pressure [CPAP], gastroesophageal refux disease [GERD] management) and are not candidates for an open surgical procedure (i.e., tracheobronchoplasty for diffuse disease or sleeve resection for focal disease) [16, 17]. Studies performed within the last 25 years have shown that airway stents improve lung function in patients with central airway obstruction and may improve survival in patients whose CAO is due to malignant disease. In this section, we will describe the indications of stent insertion based on the mechanism of obstruction.

2These include rigid or fexible bronchoscopic resection, laser, electrocautery, cryotherapy, photodynamic therapy, or brachytherapy and are described in detail in other chapters in this book.

Extrinsic Compression

Extrinsic compression from benign or malignant thyroid disease, primary lung tumors (Fig. 16.2), mediastinal masses, or massive intrathoracic lymphadenopathy is the most common indication

a

for airway stent insertion. Rarely, vascular abnormalities such as aortic aneurysm, vascular sling, and double aortic arch may cause symptomatic extrinsic airway obstruction and may require stent insertion for patients who do not undergo corrective surgery.

b

Fig. 16.2  Indications for airway stent insertion. Severe extrinsic compression of the right mainstem bronchus due to primary lung cancer, before (a) and after (b) silicone stent insertion. Severe, complex post tracheostomy, triangular or A-shaped stenosis with malacia in a non-surgical candidate before (c) and after (d) a 16 × 40 mm straight silicone stent was inserted. Follow up bronchoscopy triggered by excessive coughing and inability to raise secretions dem-

onstrated restored tracheal patency but the stent migrated down to the main carina (e) and required removal. Benign gastro-tracheal stula (f) after esophagectomy and gastric pull up procedure. As repeat surgery was unsuccessful at closing the stula, a fully covered SEMS was used (g). Four weeks later the stent was removed and fortunately, the airway wall completely healed (h) without recurrence of thestula during the follow up

Intraluminal Obstruction

Stent insertion may be useful in selected cases of endoluminal exophytic benign central airway obstruction (CAO); this is the case of refractory endobronchial recurrent respiratory papillomatosis (RRP) when medical and other endobronchial therapies fail to restore airway patency. Case reports show that papilloma debulking and silicone stents can offer adequate control of symptoms [18]. However, histologically benign intraluminal obstruction necessitating stent insertion is mostly caused by strictures, either idiopathic or related to other disorders. The most common cause of benign strictures is post-­ intubation and post-tracheostomy stenosis (Fig. 16.2), but it is important to note that a variety of other conditions associated with strictures should be ruled out before making the diagnosis of idiopathic stenosis. This is relevant as the management strategies need to be individualized. Examples include granulomatosis with polyangiitis (GPA), amyloidosis, sarcoidosis, ulcerative colitis, post-tuberculosis, or due to Klebsiella rhinoscleromatis infection. For example, 12 to 23% of patients with GPA develop tracheobronchial stenosis. A multicenter retrospective study of 47 patients with GPAassociated tracheobronchial stenosis found that these patients bene t from a delay in any interventional procedures following the diagnosis, allowing for a “cooling off” period from the associated infammation. It is also advisable to have patients on an increased dose of corticosteroids to >30 mg/day during the peri-procedural period [19]. Studies suggest that subglottic stenosis (SGS) can prove refractory to pharmacologic therapy alone with up to 62% patient experiencing a relapse on conventional GPA therapy [19]. Laryngotracheal resection with reconstruction in patients with GPA has been associated with disease relapse even in a highly selective group with 55 to 75% patients requiring additional tracheal dilation and 9 to 13% patients requiring a permanent tracheostomy [20, 21]. Therefore, stent insertion should be considered for patients with pharmacologically refractory GPA who require multiple dilations,

The remainder of this section will focus on the role of stent insertion for benign stenoses associated with intubation (PITS) and tracheostomy (PTTS). The incidence rate of benign tracheal stenosis following intubation has historically ranged from 0.6 to 19% and following tracheostomy from 6 to 65%. Fortuitously the advent of low-pressure cuffs has substantially decreased these rates (by up to tenfold), yet still 1–5% of patients suffer from traumatic symptomatic PITS or PTTS, typically occurring 2–3 months following the event [22]. It remains to be determined whether the introduction of new mechanical ventilators with continuous endotracheal cuff pressure monitoring or the low pressure, low volume tracheostomy tubes could further reduce the incidence of PITS.

The true incidence of PITS in patients requiring mechanical intubation due to coronavirus disease 2019 (COVID-19) is unknown. However, prolonged intubations frequently followed by tracheostomy, prone mechanical ventilation, and possible endotracheal tube (ETT) cuff overinfation due to lack of proper surveillance in overwhelmed healthcare facilities might contribute to a higher incidence of PITS in COVID-19 patients [23]. Furthermore, shared risk factors between PITS and severe COVID-19 pneumonia, such as obesity and diabetes, may also justify this association. More investigation is needed to understand the exact pathophysiology of PITS in patients who underwent mechanical intubation for severe COVID-19, speci cally the role of infammation in the development of scarring within airway mucosa [24].

For post-intubation or post-tracheostomy strictures, stent placement should be considered only in inoperable patients; in addition, patients need to be symptomatic and the lumen of the airway below half of its normal after other interventional endoscopic techniques have been applied. We believe these patients are better served by a multidisciplinary airway team consisting of interventional­ pulmonologists, thoracic surgeons and otolaryngologists [25].

Benign airway obstruction can be classi ed in a variety of ways, and management techniques and success rates vary based on the type of steno-

sis. For example, a simple web-like stricture (vertical extent less than 1 cm), which is dilated and does not recur, will not require a stent [26, 27]; a complex stricture, however, often has associated chondritis, and dilation alone (with or without laser assistance) is not usually successful and a stent would be required to maintain airway patency [28]. Another way of classifying strictures uses the terms “structural” and “dynamic”: a structural stenosis is a result of scarring andxed constriction of the airway, which is the most common form. A dynamic stenosis is a form of focal, localized malacia with degree of obstruction dependent on the variability of transthoracic pressures during respiration. Another classi cation has been proposed: that of a dynamic A-shape tracheal stenosis (DATS) which is an amalgamated variation that combines both a structural stenosis from a fractured anterior cartilage ring with a dynamic stenosis from posterior malacia (Fig. 16.2). This results in a triangular “A-shaped” trachea on imaging. This is an important nding as the structural component is not the result of scaring/shrinkage of the trachea and as such the management of DATS differs signi - cantly from that of other structural forms of benign airway strictures. Speci cally, patients with DATS do not bene t from dilation alone. At the same time, due to the dynamic component to the stenosis, patient experiences higher rates of stent migration than typical structural stenosis patients (Fig. 16.2) [22].

Silicone stent insertion performed using rigid bronchoscopy under general anesthesia is considered an acceptable alternative to surgery for inoperable patients with complex tracheal strictures. A 2016 retrospective study of 90 patients undergoing stenting for histologically benign airway obstruction showed that in patients with simple stenosis undergoing stenting there was a 100% success rate with a single stent placed and mean stent duration of 5.6 months. On the other hand, patients with complex stenoses did not fare as well: 45% required multiple re-stenting procedures, 60% required stent repositioning, the stents remained in place for 12 months, and despite this the success rate was 70% at 1 year [27]. In an older study of 42 patients with complex stenoses, only 9 were surgi-

cal candidates and 33 were treated with silicone stent insertion, with a success rate of 69% [29]. The success rate of bronchoscopic treatment once stents are removed (usually after at least 6 months) in cases of complex stenosis is reportedly low (17.6%) suggesting the need for long-term indwelling airway stent. A higher rate of airway stability after stent removal (46.8%, in 22 out of 47 patients) was described after stents remained in place for a longer period of time (mean of 11.6 months) [30], with almost 50% of patients (12/22) having their stents for more than 12 months. We thus propose a trial of stent removal at 1-year post-­insertion understanding that patients with recurrence may need to be reconsidered for open surgical intervention or need long-term indwelling airway silicone stents.

Predictors of success of bronchoscopic treatments are stenoses shorter than 1 cm in vertical extent and without associated malacia (i.e., chondritis). Lesion extent (i.e., height) and intubation-­to-­treatment latency have also been reported to independently predict the success of bronchoscopic intervention. In one study, 96% of patients with lesions <3 cm in height were successfully treated bronchoscopically, but the success rate decreased to 20% for lesions longer than 3 cm. Patients with stenosis present for more than 6 months since the original injury were also less likely to be successfully treated bronchoscopically [31], suggesting that the established brotic tissue counteracts the expansile force of the remaining cartilage [32]. In fact, knowing the integrity of the cartilage in post-intubation or post-tracheostomy stenoses is important in the treatment decision-making process. In complex post-intubation/tracheostomy stenosis, cartilage integrity or lack thereof is not always easily assessed on white light bronchoscopy, mainly because of the overlying stenotic hypertrophic tissues [33] (Fig. 16.3). To assess the integrity of the cartilage, one may use high frequency ­endobronchial ultrasound (20 MHz balloon based radial probe) during the bronchoscopic intervention. The EBUS image using this system has a high resolution and allows visualization of the stenotic tissue and the cartilaginous structures and may be a surrogate of gross

Fig. 16.3  Rigid bronchoscopic and sonographic view of laryngotracheal stenosis. In the upper panel, the circumferential post intubation tracheal stenosis is noted but on white light imaging, the cartilage cannot be assessed. High frequency endobronchial ultrasound (20 MHz probe) can identify the cartilage and its disruption. The knowledge that the cartilage is affected could impact man-

agement since simple laser assisted mechanical dilation without stent insertion is unlikely to be maintain airway patency in the long term. In the lower panel, idiopathic subglottic stenosis at the level of the cricoid is seen on white light imaging, but the intact cricoid cartilage itself is only identi ed on high frequency endobronchial ultrasound

histology for tracheal stenosis; for instance, in idiopathic tracheal stenosis, the cartilage is known to be normal, but there is clear hypertrophy of the mucosa and submucosa as visualized by EBUS as well. On the other hand, in complex stenoses, there is partial or total destruction of cartilage histologically which can be identi ed by EBUS [33] (Fig. 16.3). Since the balloonbased radial EBUS probe is not available on all markets, proceduralists could consider using the linear EBUS, but there is no data about its abil-

ity to de ne tracheal stenosis complexity or guiding management in this disease.

When used for benign stenosis, silicone stents are preferable and can be helpful for splinting post-intubation/tracheostomy stenoses and are considered appropriate to palliate airway narrowing in nonsurgical candidates 3 [28, 34, 35]. Stent-­

3Coexistent diseases: coronary heart disease, severe cardiac or respiratory insuf ciency, or poor general condition or stenosis length >4 cm.

related complications, however, are not uncommon in this disease and include migration, obstruction from secretions, infection, and signi cant granulation tissue formation at the proximal or distal extremities of the stent [14, 36].

Silicone T-tubes (Montgomery T tubes) or tracheostomy tubes are sometimes used for benign tracheal strictures, especially when they involve the cricoid cartilage; they should be inserted through the area of stenosis, if possible, to conserve airway not involved by the stenotic lesion. For most patients who do not require mechanical ventilatory support, a silicone T-tube could provide symptomatic improvement [37]. These therapies are warranted in the few patients with critical stenoses who are neither candidates for surgery nor for indwelling airway stent insertion or for who develop recurrence after such interventions [28]. T-tubes can also be used when tracheal resection and reconstruction or dilation techniques are either not available or have failed, or as a solution for patients who had silicone stent placement complicated by frequent migrations [36]. In a large case series including 53 patients with complex tracheal stenoses (24 post-­ tracheostomy), silicone T-tube insertion was effective in 70% of patients with limited complications [38]. The sharper edge of the proximal aspect of the T-tube, in cases when it has to be cut, suboptimal tracheostomy tract (i.e., non-­ midline stoma), as well as its placement within 0.5 cm from the vocal cords are known risk factors for granulation tissue development 4 [38]. In addition, airway secretions may become dry and cause obstruction. Patients, families, and referring physicians bene t from instruction on how to care for and monitor T-tubes. Frequent bronchoscopies may be necessary to remove mucus plugs, with some investigators performing three to four biweekly bronchoscopies, followed by once every 4 weeks once stent patency has been documented [38].

4Granulation tissue formation at the proximal end of the T-tube has also been described and it is believed that chronic airway irritation incites infection and promotes or aggravates granulation tissue formation.

The inherent disadvantage of a T-tube is the need for a tracheostomy. It also requires patient compliance with pulmonary hygiene measures including but not limited to saline nebulization, deep breathing exercises, and self-suctioning. In our opinion, T-tubes should be used for patients who are not surgical candidates for open resection and when endoluminal stent placement is associated with frequent stent-related complications.

Self-expandable metallic stents (SEMS) have been associated with signi cant complications and are to be avoided, if possible, in benign disorders. Immediate symptomatic improvement is reported and expected, but the long-term complications are common and may be life threatening [39]. In one study of 30 patients who underwent SEMS for benign tracheal stenosis, half of the patients required stent removal due to complications, with migration being the most frequent one. However, if there are no other options available, this report suggests that it is safe to proceed with SEMS and remove the stent after 4 months [40].

Self-expandable silicone stents, contrary to metal stents, have the advantage of being easily removable. They are, however, placed under rigid bronchoscopy or suspension laryngoscopy. Some of these silicone stents have been studied in benign airway obstruction including tracheal stenosis and malacia [30]. While immediate symptom palliation was established in most cases, the incidence of complications was high (75%) with stent migration occurring in 69% of cases [41, 42]. One such particular device, the Polyfex Stent (Boston Scienti c) is no longer manufactured or available on the market.

Postoperative Tracheobronchial

Stenosis (POTS)

A variant of histologically benign tracheal stenosis, postoperative tracheal stenosis (POTS) is a challenging problem following tracheal resection­. Despite improved recognition and surgical techniques, the rate of POTS is 2–9% following tracheal resection. The majority of patients with POTS are not candidates for further surgical man-

agement due to a combination of high general surgical risk, poor lung function, and technical dif culties associated with previously resected tracheal segments. As such, bronchoscopic intervention is considered a therapeutic option. In a single-center retrospective review, 30 patients with POTS managed by bronchoscopic intervention were studied and included dilations (balloon or bouginage), YAG laser, and stenting (63% underwent silicone stents, no metallic stents were used). The majority (97%) achieved improvement in dyspnea within 24-h post-­procedure. Stents were successfully removed in 37% of patients. Average stent duration in those amenable to removal was 7 months; 16% of those with stents removed developed tracheomalacia [43].

Mixed Obstruction: Malignant

Central Airway Obstruction

Malignant central airway obstruction (CAO) is a frequent complication of primary lung cancer and other tumors that metastasize to the chest (especially breast, colon, melanoma, and renal cell cancers). Malignant CAO can be intrinsic (endobronchial/intraluminal), extrinsic, or mixed, which has features of both intrinsic and extrinsic compromise. The most common form of malignant CAO is a mixed obstruction [44]. In a series of 172 patients who underwent stent insertion for malignant CAO at a cancer institution, 62.5% of the stents were placed for mixed disease, while only 16.4% and 14.8% were placed for extrinsic compression and intraluminal obstruction, respectively [14]. In general, the management principles for malignant intraluminal obstruction are the same as those for benign disease: if there is still obstruction after recanalization with various ablative techniques, if extrinsic compromise is present, or if there is a loss of airway structure (i.e., severe malacia due to cartilage invasion and destruction by tumor), a stent is placed to maintain airway patency. The impact of silicone stent placement in endoluminal lesions due to lung cancer was recently investigated in a prospective, randomized trial (SPOC). In this trial, 78 patients after therapeutic bronchoscopy

were randomized to a stent arm (n = 40) or control (n = 38). The study demonstrated that local recurrences and subsequent bronchoscopies were less frequent in the stent group comparing with controls, leading to longer lasting symptom relief. Moreover, stenting was showed to be ben- e cial only after the failure of the rst-line anti-­ cancer treatment [45].

Management of malignant CAO often requires a combination of multiple different management modalities. The choice of techniques is operator dependent and is contingent not only on the etiology of the obstruction, but also availability of various technologies. To study the impact of procedural volume and choice of technique in bronchoscopic management of malignant CAO, a large multicenter retrospective review of bronchoscopic management of patients with malignant CAO was undertaken from the American College of Chest Physicians (CHEST) Quality Improvement Registry, Evaluation, and Education (AQuIRE) registry. Overall, the study found that despite signi cant inter-institutional differences in procedural preferences and volumes, there was no impactful difference in technical success and that one speci c therapeutic modality could not be recommended over another [44]. More recently, in a study including 301 procedures for malignant CAO, factors associated with technical success of therapeutic bronchoscopy included smoking status (never smokers having better results than smokers), patent distal airway on CT and during bronchoscopy and time from radiographic nding to therapeutic bronchoscopy [46].

Interventional treatment of malignant CAO is considered to be primarily palliative as once cancer progresses to the point of CAO it is almost invariably incurable. As such, endoscopic interventions focus predominantly on attempting to improve quality of life. Relieving the CAO due to malignant disease has been proposed to prevent post-obstructive pneumonia, sepsis and septic shock; allow extubation, change in level of care, permit initiation of systemic therapy; and improve survival. There is evidence that bronchoscopic therapies often provide acute relief of the obstruction, improve quality of life, and serve as a therapeutic bridge until systemic treatments become

effective [47–49]. Prospective studies show that bronchoscopic intervention for malignant CAO is associated with improvement in the six-minute walk test (6MWT), spirometry, and dyspnea [50]. In addition, studies show that airway stent insertion resulted in signi cant palliation of symptoms in patients with malignant CAO as evaluated by Medical Research Council (MRC) dyspnea scale and performance status [51].

In the AQuIRE registry mentioned above, bronchoscopic interventions were associated with a signi cant decrease in dyspnea (decrease in Borg score by 0.9 ± 2.2). Speci cally, 48% reported clinically signi cant improvement in dyspnea, 43% reported no change, and 9% had worsened dyspnea. Of particular relevance, dyspnea improved proportionally to the pre-­ procedure severity of dyspnea. Another notablending was that those with lobar (as opposed to more central) obstruction were less likely to have much improvement in dyspnea. Bronchoscopic interventions were also associated with a signi - cant increase in health-related quality of life (HRQOL). Overall, 42% had a signi cant improvement of HRQOL, 33% remained unchanged, and 25% reported worsened HRQOL. Again, as with the predictors of dyspnea relief, a higher baseline Borg (i.e., worse baseline dyspnea) predicted a more pronounced improvement in HRQOL, while those with lobar obstruction were found to have less improvement in HRQOL [44]. While airway patency was improved in >90% of patients, less than half improved their HRQOL scores. These nding suggest that we need better prediction models for whom dyspnea and HRQOL improves after such interventions. Despite the focus on palliation and improved quality of life with these procedures, a signi cant post-procedural survival advantage was also apparent in those without severe performance limitations prior to their procedures when compared with historical controls [51].

The presence of stridor (refecting critical CAO) prior to intervention was found to be a poor prognostic indicator for survival in patients undergoing bronchoscopic intervention for malignant CAO: those without stridor had a 1 year and 2-year survival of 35.5% and 31%,

respectively, while those with stridor had a 1 year and 2 year survival of 12.5% and 0%, respectively. Patients requiring stent placement for malignant CAO as opposed to dilation +/− other non-stenting interventions had signi cantly lower 1- and 2-year survivals [52]. In another study of 74 patients with malignant CAO, extrinsic compression from esophageal cancer and stent placement correlated with poor survival [53]. It is not clear whether lower survival rates are because of the stenting or just because patients requiring stents had more severe/extensive airway obstruction.

Subsequent chemotherapy and/or radiotherapy have been shown to increase disease free survival during the rst year after restoration of airway patency [47, 54]. A retrospective single-­ center study of 48 patients with malignant CAO who underwent bronchoscopic intervention reviewed the effects of chemotherapy following bronchoscopic interventions. The patients who received post-procedural palliative chemotherapy had a median survival of 6 months with a 1 year and 2-year survival of 35% and 31%, respectively. Those patients who received no post-­ procedural chemotherapy had a median survival of 2.5 months with a 1 year and 2-year survival of 18% on 14%, respectively [52]. In addition, it appears that airway stent insertion followed by adjuvant therapy may improve survival even in treatment-naive patients with severe symptomatic airway obstruction caused by advanced lung cancer. In one study, while the performance status and dyspnea scales improved in both treatment-­naive and terminal-stage lung cancer, the median survival time and 1-year survival rate after stent insertion were 1.6 months and 5.1%, respectively, in the terminal stage group, and 5.6 months and 25.0%, respectively, in the treatment-­naive group [55].

Lung cancer patients who develop respiratory failure due to CAO have particularly poor ­prognoses: only 25% are successfully liberated from the ventilator and 40–70% die in the hospital. In addition to the quality-of-life issues, ventilated patients are often not considered candidates for additional oncologic treatment. Furthermore, patients with malignant CAO may be given low